Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is partly or completely lost. About 5% of all people suffer from diabetes and the disorder approaches epidemic proportions.
Human insulin consists of two polypeptide chains, the A and B chains which contain 21 and 30 amino acid residues, respectively. The A and B chains are interconnected by two disulphide bridges. Insulin from most other species is similar, but may contain amino acid substitutions in some positions. In the treatment of diabetes mellitus, many varieties of insulin formulations have been suggested and used, such as regular insulin, isophane insulin (designated NPH), insulin zinc suspensions (such as SEMILENTE®, LENTE®, and ULTRALENTE®), and biphasic isophane insulin. Also human insulin analogues have been developed. They are designed for particular profiles of action, i.e. fast acting or prolonged action. Commercially available products comprising such insulin analogues include LEVEMIR®, NOVORAPID®, HUMALOG®, APIDRA® and LANTUS®.
Normally, insulin formulations are administered by subcutaneous injection.
However, administration by the oral route would be advantageous due to patient compliance, safety and convenience.
Oral administration of protein drugs such as insulin often results in very low bioavailability due to several barriers such as enzymatic degradation in the gastrointestinal (GI) tract, drug efflux pumps, insufficient and variable absorption from the intestinal mucosa, as well as first pass metabolism in the liver. Human insulin is degraded by various digestive enzymes found in the stomach (pepsin and gastricsin), in the intestinal lumen (chymotrypsin, trypsin, elastase, carboxypeptidases, etc.) and in mucosal surfaces of the GI tract (aminopeptidases, carboxypeptidases, enteropeptidases, dipeptidyl peptidases, endopeptidases, etc.). Recent formulation designs for oral protein/peptide delivery include co-formulations with protease inhibitors, permeation enhancers, polymer-based delivery systems and insulin conjugates. The latter includes hexyl-insulin-monoconjugate-2 (HIM2) (Nobex Cooperation and GSK), a human insulin analogue with a PEG 7-hexyl group attached to B29. In for example U.S. Pat. No. 7,030,082, U.S. Pat. No. 6,867,183 and U.S. Pat. No. 6,770,625 oral HIM2 has been reported to have increased proteolytic stability and bioavailability compared to insulin.
Combination of a protease resistant insulin analogue with an oral protein delivery system represents a promising strategy for oral insulin administration. Furthermore no enzyme inhibitors need to be incorporated in the delivery system.